Antinflammatory compositions and methods

ABSTRACT

An improved antiinflammatory composition and method of treating inflammation which employs a combination of antiinflammatory piroxicam, or a pharmaceutically acceptable salt thereof, with analgesic acetaminophen, antidepressant doxepin, bronchodilator pirbuterol, minor tranquilizer diazepam, or antihypertensive trimazosin.

CROSS REFERENCE TO RELATED APPLICATION

This application is a division of co-pending application Ser. No.179,829, filed Apr. 11, 1988, which is a division of application Ser.No. 941,140, filed Dec. 12, 1986, now U.S. Pat. No. 4,766,117, which isa division of Ser. No. 821,183, filed Jan. 21, 1986, now U.S. Pat. No.4,672,061, which is a division of application Ser. No. 695,590, filedJan. 28, 1985, now U.S. Pat. No. 4,579,846, which is acontinuation-in-part of application Ser. No. 659,602, filed Oct. 11,1984 now abandoned.

BACKGROUND OF THE INVENTION

The present invention is concerned with an improved antiinflammatorycomposition and method of treating inflammation which employsantiinflammatory piroxicam, or a pharmaceutically acceptable saltthereof (particularly the ethanolamine salt) in combination withanalgesic acetaminophen, antidepressant doxepin, bronchodilatorpirbuterol, minor tranquilizer diazepam, or antihypertensive trimazosinor a related compound. The generic names used here and elsewhere hereinare from the USAN and the USP Dictionary of Drug Names, 1961-1981,Griffiths et al., ed., U.S. Pharmacopeial Convention Inc., Rockville,Md., 1984, have subsequently been assigned and published as officialUSAN names, and/or appear in The Merck Index 10th Edition.

Gastrointestinal irritation, including ulcers, is a side effect commonlyassociated, to one degree or another, with antiinflammatory agents. Inmany cases, individuals requiring such antiinflammatory treatment areprecluded from enjoying the benefits thereof because of theirsusceptibility to such side effects. The present combination ofpiroxicam with one or another of the medicinal agents defined abovepermits desirable antiinflammatory therapy while preventing orameliorating said gastrointestinal irritation or ulcers.

Acetaminophen has been previously reported to reduce the ulcerogenicityof aspirin [Sugers et al., J. Pharm. Pharmacol. 30, 84 (1978); ibid. 31,840 (1979); and Adv. Prost. Thromb. Res. 8, 1547 (1980)], or ofacidified aspirin [Konturek et al., Gut 23, 536 (1982)]. However,indomethacin reversed the protective effect of acetaminophen when givenwith acidified aspirin (loc. cit.). In later studies, it was reportedthat acetaminophen reduced the ulcerogenicity of indomethacin andaspirin, but not of phenylbutazone or glafenine, and of ibuprofen onlyat the highest dose (800 mg/kg) of the latter compound [van Kolfschotenet al., Agents Actions 12, 247 (1982); Toxicology Applied Pharm. 69, 37(1983)]. Acetaminophen in combination with ketoprofen and otherparticular antiinflammatory agents has been reported to provide ananalgesic effect which is greater than a simple additive effect (U.S.Pat. Nos. 4,233,313 to 4,233,317; 4,234,601; 4,207,340; and 4,242,353).While we are aware of no literature reports concerning the combinationof acetaminophen with piroxicam or any other oxicam for any purpose, wehave been advised that a piroxicam-acetaminophen combination has beenrecently marketed in Argentina.

Bronchodilators salbutamol (albuterol), phenylephrine and isoproterenol,but not propranolol, have been reported to inhibit formation ofindomethacin-induced ulcers in animals [Fielding et al., Eur. Surg. Res.9, 252 (1977); Kasuya et al., Japan J. Pharmacol. 29, 670 (1979)]. Inanother study, administration of isoproterenol to a chambered section ofa dog's fundus reduced or prevented aspirin-induced tissue damage[McGreevy et al., Surg. Forum 28, 357 (1977)]. There are no known priorreports concerning the effect of bronchodilator pirbuterol onantiinflammatory agents.

Antidepressant doxepin has also been reported to have gastricantisecretory activity and to be as effective as cimetidine in thetreatment of duodenal ulcers in humans [Hoff et al., Curr. Med. Res.Opin. vol. 6, supplement 9, page 36 (1980); Scand. J. Gastroent. 16,1041 (1981)]. It has also been reported that doxepin shows antiulcer andantisecretory activity in rats and dogs; and that it significantlyreduced the ulcerogenic potential of indomethacin, diclofenac andaspirin in water-immersion restraint-stressed rats [Leitold et al. Arch.Pharmacol. 316 (supplement), R50, abstract 199 (1981); Leitold et al.,Advances in Experimental Ulcers, Umehara and Ito, editors, ICEU, Tokyopp. 27-36 (1982); Arzneim-Forsch/Drug Res. 34, 468 (1984)].

Major tranquilizer and antipsychotic chlorpromazine has been reported toreduce indomethacin-induced gastric ulcers in rats [Kasuya et al. loc.cit. (1979)]. However, there are no known prior reports concerning theuse of an antihypertensive agent such as trimazosin or a minortranquilizer such as diazepam in reducing gastric side-effects inducedby nonsteroidal antiinflammatory agents.

Phospholipids have also been reported to reduce gastrointestinaldistress (damage to the mucous membrane, gastric ulcer formation) whencombined with nonsteroidal antiinflammatory agents, particularlyphenylacetic or phenylpropionic acid derivatives such as ibuprofen,naproxen, diclofenac and fluribprofen [Ghyczy et al., U.S. Pat. No.4,369,182 (1983)], as have antiulcer pirenzepine [Leitold et al.,Therapiewoche 27, pp. 1532-1548 (1977); German Patent Application No.2,708,520] and histamine-H₂ antagonist (gastric acid antisecretory,antiulcer) compounds such as ranitidine, cimetidine and1-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]-propylamino]]-1H-1,2,4-triazole-3-methanol,which have been previously combined with indomethacin and otherantiinflammatory agents for this purpose. See, for example, U.K. PatentApplication Nos. 2,105,193 and 2,105,588; and Lovelace, U.S. Pat. No.4,230,717.

U.S. Pat. No. 4,567,179 by Lombardino, filed concurrently with thegreat-great-great grandparent of the instant application, describesimproved antiinflammatory salts of piroxicam, including those withtrimazosin, doxepin, N-demethyldoxepin, isoproterenol and pirbuterol.

SUMMARY OF THE INVENTION

The present invention concerns an improved anti-inflammatory compositionwhich comprises an anti-inflammatory amount of piroxicam, or apharmaceutically acceptable salt thereof (particularly the ethanolaminesalt), in combination with a piroxicam-induced gastric irritation andulcer inhibiting amount of a compound selected from the group consistingof acetaminophen, doxepin, pirbuterol, diazepam, fanetizole, trimazosinand related compounds, and the pharmaceutically-acceptable saltsthereof.

The present invention is also concerned with an improved method for thetreatment of inflammation in a mammal, including man, which comprises,in addition to treatment with an antiinflammatory amount of piroxicam,treatment with a gastric antiirritation and ulcer inhibiting amount ofacetaminophen, doxepin, pirbuterol, diazepam, fanetizole, trimazosin, ora pharmaceutically-acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The antiinflammatory agent of the present invention, piroxicam, isknown. For example, The Merck Index 10th Ed., 1983 contains a monographconcerning piroxicam (no. 7378), as does the Physicians' Desk Reference(PDR), 38th Ed., pp. 1556-1557 (1984). The preferred ethanolamine saltof piroxicam is specifically disclosed in U.S. Pat. No. 4,434,164.

The compounds of the present invention which we have found to inhibitpiroxicam-induced gastric irritation and ulcers are also knowncompounds. Acetaminophen is a proprietory analgesic (The Merck Index10th Ed., monograph no. 39; see also the PDR, 38th Ed., p. 2096).Doxepin is an antidepressant, marketed in the form of its hydrochloridesalt (The Merck Index 10th Ed., monograph no. 3434; PDR 38th Ed., pp.1688-1689). Pirbuterol is a bronchodilator marketed or to be marketedaround the world in the form of its dihydrochloride and monoacetatesalts. See The Merck Index 10th Ed., monograph no. 7364. Its earlysynthesis and utility as a bronchodilator is disclosed in U.S. Pat. Nos.3,700,681; 3,763,173; 3,772,314 and 3,786,160. Alternatively andgenerally improved syntheses are found in U.S. Pat. Nos. 3,948,919;4,011,231; and 4,031,108; Luxembourg Patent No. 79564; and EuropeanPatent Application Nos. 58069, 58070, 58071 and 58072. More recently,pirbuterol has also found utility in the treatment of congestive heartfailure (U.S. Pat. No. 4,175,128 ). Diazepam is a widely prescribedminor tranquilizer (The Merck Index 10th Ed., monograph no. 2967; PDR38th Ed., pp. 1671-1674). Trimazosin (The Merck Index 10th Ed.,monograph No. 9506) is an antihypertensive agent, marketed or to bemarketed around the world as a hydrochloride salt, which is structurallyrelated to prazosin.

The clinical value of the present improved formulation in inhibitingpiroxicam-induced gastric irritation and ulcers is reflected byappropriate animal studies. Typical experimental protocols, in which theability of the test compound to prevent or reduce piroxicam-inducedgastric lesioning was determined, are found in the specific Examplesbelow.

The present invention is readily carried out. The piroxicam or its saltis dosed in a mammal, particularly man, in the range of 0.1 to 1mg/kg/day. The second medicinal agent can be dosed separately, in whichcase the latter will be employed in an amount within (but generallylower in) the dosage range and according to dosage regimens (frequency,routes and compositions) as specified for their alternative utility inthe prior art, for example, in references cited above or further citedin said references.

Preferably and conveniently, the piroxicam and a gastric irritation andulcer inhibiting agent of the present invention are co-administered in asingle, combined formulation. This can be in a form suitable forparenteral administration, but is preferably in a form suitable for oraladministration. The proportion of each drug in the combined dosage formwill be in the ratio of the total daily dosage of each drug when dosedalone. The combined drugs will be dosed in single or divided doses.Single daily dosage will be most preferred in those cases where the invivo half-life of the second medicinal agent is (like that of piroxicam)relatively long, and where the daily dosage of the second agent for atypical adult patient is relatively small, e.g., less than 1-2 grams.

In the preferred oral route of dosage, the amount of piroxicam (or saltequivalent) for an average adult patient will generally be in the rangeof 5-50 mg/day in combination with:

200 to 4000 mg/day of acetaminophen;

4 to 200 mg/day of doxepin;

3 to 100 mg/day of pirbuterol;

2 to 40 mg/day of diazepam; or

4 to 500 mg/day of trimazosin;

an amount of the second medicinal agent generally sufficient to inhibitgastrointestinal irritation or ulcers which could otherwise be inducedby the piroxicam in patients susceptible to this side effect.

The combined compounds are administered alone or in further combinationwith pharmaceutically-acceptable carriers or diluents. For oral use,suitable pharmaceutical carriers include inert diluents or fillers,thereby forming dosage forms such as tablets, powders, capsules, and thelike. These pharmaceutical compositions can, if desired, containadditional ingredients such as flavorings, binders, excipients and thelike. For example, tablets containing various excipients, such as sodiumcitrate, are employed, together with various disintegrants such asstarch, alginic acid and certain complex silicates, together withbinding agents such as polyvinylpyrrolidone, sucrose, gelatin andacacia. Additionally, lubricating agents such as magnesium stearate,sodium lauryl sulfate and talc are often useful for tabletting purposes.Solid compositions of a similar type may also be employed as fillers insoft and hard filled gelatin capsules. Preferred materials thereforinclude lactose or milk sugar and high molecular weight polyethyleneglycols.

The present invention is illustrated by the following examples. However,it should be understood that the invention is not limited to thespecific details of these examples.

EXAMPLE 1 Protective Effect of Various Medicinal Agents onPiroxicam-Induced Gastric Lesions in Rats

Adult male "specific pathogen free" rats weighing 140-160 grams of theCD strain (Sprague-Dawley) were obtained from Charles River BreedingLaboratories (Kingston, N.Y.). The animals were acclimated forapproximately one week and tested when they reached a body weight of200-225 grams. The rats were fasted for 16 hours and randomized intogroups consisting of 8 to 20 animals which were normalized with regardto their average body weight.

Gastric ulcers were induced in the animals by orally dosing them with asingle 100 mg/kg dose of piroxicam in 2 ml. of aqueous 0.1%methylcellulose (pH=6.8). Those animals receiving a second medicinalagent separately received the second drug in an additional 2 ml. of thesame medium at about the same time. Six and one-half hours later, theanimals were sacrificed by cervical dislocation and autopsied. Thestomachs were surgically removed, dissected along the greater curvatureand rinsed with cold water. The stomachs were individually scored forboth linear and punctate lesions. The total number of lesions was usedfor scoring purposes. The data obtained from each group of rats wereanalyzed after calculation of the mean number +/- the standard error oftotal gastric lesions. The values obtained were also compared to thecontrols which received only piroxicam by the two-tailed Student'sT-Test for non-paired data. The protective effect of the secondmedicinal agent against piroxicam-induced ulcers is shown in Table I.These data show that pirbuterol, acetaminophen, doxepin and diazepameach significantly reduce piroxicam-induced gastric lesions in thehealthy fasted rat.

                  TABLE I                                                         ______________________________________                                        Protective Effect of Various Medicinal Agents                                 on Piroxicam-Induced Gastric Lesions in Rats.sup.a                                                No. of             Signifi-                               Medicinal Oral Dose Rats     Lesions/Rat                                                                             cance                                  Agent.sup.a                                                                             (mg/kg)   in Group (.sup.--X +/- SE).sup.b                                                                 p 0.05.sup.c                           ______________________________________                                        (Control) --        20       10.1 (1.5)                                       Pirbuterol                                                                              3.3       10       2.8 (0.9) +                                                10        20       4.5 (1.1) +                                                33        20       2.6 (0.7) +                                      (Control) --        10       4.1 (1.0)                                        Acetaminophen                                                                           100       10       4.6 (1.9) -                                                333       10       1.4 (0.7) +                                                1000      10       0.7 (0.5) +                                      (Control) --        20       9.5 (1.1)                                        Doxepin   3.3       10       4.4 (1.0) +                                                10        10       3.6 (1.0) +                                                33        20       4.2 (1.0) +                                      (Control) --        20       9.3 (1.3)                                        Diazepam  10        20       5.6 (1.1) +                                                33        20       4.2 (1.1) +                                      ______________________________________                                         .sup.a All animals, including controls, received 100 mg/kg of piroxicam.      .sup.b Represents the mean value .sup.--X +/- the standard error (SE).        .sup.c As determined by the Student's two tailed Ttest for nonpaired data                                                                              

EXAMPLE 2

Protective Effect of Various Medicinal Agents on Gastric Lesions in RatsInduced by the Ethanolamine Salt of Piroxicam

According to the proceeding Example, gastric ulcers were induced by asingle dose of 100 or 120 mg./kg. of the ethanolamine salt of piroxicam.Test groups received various doses of various medicinal agents as shownin Table II. These data show that the test compounds showed asignificant reduction in gastric lesions induced by the ethanolaminesalt of piroxicam in healthy, fasted rats.

                  TABLE II                                                        ______________________________________                                        Protective Effect of Various Medicinal Agents                                 on Gastric Lesions Induced by the Ethanolamine                                Salt of Piroxicam                                                                        Oral     No. of            Signifi-                                Medicinal  Dose     Rats in Lesions/Rat                                                                             cance                                   Agent      (mg/kg)  Group   (.sup.--X +/- SE).sup.b                                                                 p < 0.05.sup.c                          ______________________________________                                        (Control).sup.a                                                                          --       20      6.5 (0.9)                                         Acetaminophen.sup.a                                                                      100      20      4.8 (1.0) -                                                  333      20      0.9 (0.4) +                                                  1000     20      2.0 (2.3) +                                       (Control).sup.a                                                                          --       30      7.7 (1.0)                                         Doxepin.sup.a                                                                            1.0      30      4.3 (0.7) +                                                  3.3      30      3.4 (0.6) +                                                  10       30      5.1 (0.8) -                                       (Control).sup.a                                                                          --       10      6.4 (1.1)                                         Diazepam.sup.a                                                                           10       10      5.1 (0.9) -                                                  33       10      1.5 (0.7) +                                       (Control).sup.d                                                                          --       10      7.6 (0.7)                                         Trimazosin.sup.d                                                                         3.3      10      5.0 (1.6) -                                                  10       10      3.9 (1.0) +                                                  33       10      5.2 (1.3) -                                       ______________________________________                                         .sup.a All animals, including controls, received 100 mg/kg of the             ethanolamine salt of piroxicam.                                               .sup.b Represents the mean value .sup.--X +/- the standard error (SE).        .sup.c As determined by the Student's two tailed Ttest for nonpaired data     .sup.d All animals, including controls, received 120 mg/kg of the             ethanolamine salt of piroxicam.                                          

EXAMPLE 3 Protective Effect of Acetaminophen on Piroxicam-InducedGastric Lesions in Rats

Male rats (Sprague-Dawley) having an average weight of 190 gms. wereused in these studies. Animals were fasted overnight and then dosed withtest compound suspended in 0.1% methylcellulose. Six and one-half hoursafter the administration of piroxicam or the combination, the rats weresacrificed in the same order as they were dosed. Their stomachs wereexcised, rinsed under running water and stored overnight between twosaline soaked towels. The next morning the stomachs were evaluated andgiven an ulcer score. For each lesion a number was assigned according tosize and another for intensity. The product of the two numbers is calledthe intensity factor, and the summation of the intensity factorsrepresented the ulcer score for that stomach. Two separate (one wasblind) runs were performed to obtain the data contained in Table III.The data show that acetaminophen attenuated the lesioning effect of 32mg./kg. of piroxicam in healthy rats and that the protection is dosedependent.

Separate studies, in which piroxicam was dosed at 32 mg./kg., p.o. andacetaminophen at 250 mg./kg., p.o. or s.c., demonstrate thatacetaminophen had no effect on the plasma levels of piroxicam.

Rats pre-dosed with acetaminophen (250 mg./kg., p.o.) at 16 and 3 hoursbefore receiving piroxicam (32 mg./kg., p.o.), were not significantlyprotected from G.I. lesioning induced by the piroxicam under thisprotocol.

                  TABLE III                                                       ______________________________________                                        Dose Response of Acetaminophen With Piroxicam.sup.a                           Dose of Drug (mg/kg, p.o.)  Mean Ulcer                                        piroxicam                                                                             acetaminophen                                                                             Number of Rats                                                                            Score + S.E.M.                                ______________________________________                                         0       0           4          0.0 ± 0.0                                  32       0          16          8.1 ± 0.8                                                      10          (14.0 ± 1.7)                               32       50         16          11.1 ± 1.6                                 32      100         16          10.2 ± 1.4                                                     10          (10.8 ± 0.8)                               32      200         16          2.7 ± 0.7                                  32      400         16          1.0 ± 0.4                                   32.sup.b                                                                              800.sup.b  16          1.2 ± 0.8                                   0      100          8          0.3 ± 0.2                                   0      320         16          0.7 ± 0.2                                  ______________________________________                                         .sup.a This study was run blindly, except bracketed data, which was from      preliminary, unblinded study.                                                 .sup.b Several of the rats dosed with 32 mg/kg of piroxicam and 800 mg/kg     of acetaminophen had stomachs that were slightly distended with gas.     

EXAMPLE 4 Prophylactic and Therapeutic Effect of Doxepin andAcetaminophen on Gastric Lesions in Rats Induced by the EthanolamineSalt of Piroxicam

Following the method of Examples 1 and 2, with sacrifice 6.5 hourspost-dose of 100 mg/kg of the ethanolamine salt of piroxicam, thedoxepin or acetaminophen were dosed prophylactically (8-24 hours priorto sacrifice) or therapeutically (1 to 4 hours prior to sacrifice).Results are shown in Table IV. Under this protocol, acetaminophen showedconsistent protective activity when dosed 1.5 hours prior to piroxicamadministration.

                  TABLE IV                                                        ______________________________________                                        Prophylactic and Therapeutic Properties of                                    Doxepin and Acetaminophen on Gastric Lesions                                  Induced by the Ethanolamine Salt of Piroxicam.sup.a                                     Time                                                                          (hours)  Oral               Signifi-                                Compound  Prior to Dose     Lesions/Rat                                                                             cance                                   Tested.sup.a                                                                            Sacrifice                                                                              mg/kg    .sup.--X ± (SE)                                                                      p < 0.05                                ______________________________________                                        (Control) --       --       8.8 (2.2)                                         Doxepin   24       1.0      4.9 (1.5) -                                                          3.3      8.8 (1.6) -                                       (Prophylactic-     10.0     4.7 (2.2) -                                       prior to  20.5     1.0      7.0 (1.6) -                                       piroxicam          3.3      10.5 (2.5)                                                                              -                                       administration)    10.0     7.3 (1.1) -                                                 8.0      1.0      4.6 (0.9) -                                                          3.3      4.4 (1.6) -                                                          10.0     5.2 (1.0) -                                       (Control) --       --       7.3 (1.2)                                         Doxepin   4.0      1.0      3.0 (1.1) +                                                          3.3      3.6 (1.1) +                                       (Therapeutic-      10.0     3.2 (1.3) +                                       after     2.5      1.0      2.2 (0.8) +                                       piroxicam          3.3      4.1 (1.3) -                                       administration)    10.0     3.1 (0.9) +                                                 1.0      1.0      3.5 (1.2) +                                                          3.3      6.6 (1.2) -                                                          10.0     7.0 (1.1) -                                       (Control) --       --       6.2 (0.9)                                         Acetaminophen                                                                           20.5     100      3.9 (1.1) +                                                          333      9.8 (1.5) -                                       (Prophylactic)     1000     12.4 (2.0)                                                                              -                                                 8.0      100      2.7 (1.0) +                                                          333      2.2 (0.8) +                                                          1000     2.9 (1.0) +                                       ______________________________________                                         .sup.a All animals, including controls, received 100 mg/kg of the             ethanolamine salt of piroxicam 6.5 hours before sacrifice.               

EXAMPLE 5 Capsules--Piroxicam (20 mg) and Acetaminophen (1000 mg)

The following ingredients are combined in the following proportions byweight:

    ______________________________________                                        piroxicam (milled)       20                                                   acetaminophen (milled)   1000                                                 calcium carbonate        250                                                  polyethylene glycol, average                                                                           430                                                  molecular weight, 4000                                                        ______________________________________                                    

The mixture is thoroughly blended so as to obtain a uniform powder. Softgelatin capsules containing 20 mg. of piroxicam and 1000 mg. ofacetaminophen are prepared by filling suitably sized capsules with 1700mg of the blend.

To make hard gelatin filled capsules, the amount of inert ingredients isadjusted so as to conveniently fill standard sized gelatin capsulescontaining the desired amount of each active component.

EXAMPLE 6 Capsules--Piroxicam (10 mg) and Acetaminophen (500 mg)

The following ingredients are combined in the following proportions byweight:

    ______________________________________                                        piroxicam ethanolamine salt (milled)                                                                11.84   (equiva-                                                                      lent to                                                                       10 as                                                                         free                                                                          acid)                                           acetaminophen (milled)                                                                              500                                                     corn starch           485.16                                                  magnesium stearate    3                                                       ______________________________________                                    

The mixture is thoroughly blended so as to form a uniform powder. Theresultant mix is filled into appropriately sized hard gelatin capsules(fill weight 1000 mg) so as to obtain capsules containing the desiredpotency of each active ingredient.

EXAMPLE 7 Capsules--Piroxicam (20 mg) and Doxepin (15 mg) and

The following ingredients are combined in the following proportions byweight:

    ______________________________________                                        piroxicam (milled)  20                                                        doxepin hydrochloride                                                                             16     (equivalent to                                                                15 of free base)                                   polyethylene glycol, average                                                                      664                                                       molecular weight, 4000                                                        ______________________________________                                    

The mixture is thoroughly blended so as to obtain a uniform powder. Theresultant mix (700 mg fill weight) is filled into hard gelatin capsulesof a suitable size so as to obtain capsules of the desired potency.

EXAMPLE 8 Capsules--Piroxicam (20 mg) and Doxepin (50 mg)

The following ingredient are combined in the following proportions byweight:

    ______________________________________                                        piroxicam (milled)  20                                                        doxepin hydrochloride (milled)                                                                    53.3    (equiva-                                                                      lent to 50                                                                    of free base)                                     corn starch         633.7                                                     magnesium stearate  3                                                         ______________________________________                                    

The mixture is thoroughly blended to form a uniform powder which isfilled into size 0 hard gelatin capsules (fill weight 700 mg) to obtaincapsules containing the desired potency of each ingredient.

EXAMPLE 9 Tablets--Piroxicam (20 mg) and Doxepin (20 mg)

The following ingredients are combined in the following proportions byweight:

    ______________________________________                                        piroxicam (milled) 20                                                         doxepin hydrochloride                                                                            21.3    (equivalent to                                     (milled)                   20 of free base)                                   lactose            186.7                                                      hydroxypropyl methylcellulose                                                                    3                                                          sodium starch glycollate                                                                         15                                                         magnesium stearate 4                                                          ______________________________________                                    

The mixture is thoroughly blended to form a uniform powder. Measuredvolumes of the powder, corresponding to 250 mg by weight, are compressedinto tablets containing the desired potency of each active ingredient.

EXAMPLE 10 Tablets--Piroxicam (10 mg) and Pirbuterol (25 mg)

The following ingredients are combined in the following proportions byweight:

    ______________________________________                                        piroxicam ethanolamine salt                                                                       23.68   (equivalent                                       (milled)                    to 20 of free                                                                 base)                                             pirbuterol acetate  31.28   (equivalent                                                                   to 25 of free                                                                 base)                                             lactose             220.04                                                    hydroxypropyl methylcellulose                                                                     4                                                         sodium starch glycollate                                                                          16                                                        magnesium stearate  5                                                         ______________________________________                                    

The mixture is thoroughly blended to form a uniform powder. The powder,in measured volumes corresponding to 300 mg. by weight, is compressedinto tablets containing the desired potency of each active ingredient.

EXAMPLE 11 Capsules--Piroxicam (20 mg) and Pirbuterol (20 mg)

The following ingredients are combined in the following proportions byweight:

    ______________________________________                                        piroxicam (milled)                                                                              20                                                          pirbuterol dihydrochloride                                                                      26.1    (equivalent to                                      (milled)                  20 of free base)                                    cornstarch        652.9                                                       magnesium stearate                                                                              3                                                           ______________________________________                                    

The mixture is thoroughly blended so as to obtain a uniform powder. Theresultant mix (700 mg fill weight) is filled into hard gelatin capsulesof a suitable size so as to obtain capsules of the desired potency.

Equivalent proportions of piroxicam ethanolamine salt (23.7) andpirbuterol monoacetate (23.4) are combined with cornstarch and magnesiumstearate and filled into hard gelatin capsules in like manner to obtaincapsules containing the same potency of each active ingredient.

EXAMPLE 12 Capsules--Piroxicam (20 mg) and Diazepam (10 mg)

The following ingredients are combined in the following proportion byweight:

    ______________________________________                                        piroxicam ethanolamine salt                                                                      23.68   (equivalent to                                                                20 of free acid)                                   diazepam           10                                                         calcium carbonate  50                                                         polyethylene glycol, average                                                                     166.32                                                     molecular weight, 4000                                                        ______________________________________                                    

The mixture is blended to a uniform powder and filled (250 mg fillweight) into hard gelatin capsules of a suitable size to obtain capsulesof the desired potencies.

EXAMPLE 13 Tablets--Piroxicam (10 mg) and Diazepam (5 mg)

The following ingredients are combined in the following proportions byweight:

    ______________________________________                                        piroxicam            10                                                       diazepam             5                                                        lactose              123                                                      hydroxypropyl methylcellulose                                                                      2                                                        sodium starch glycollate                                                                           8                                                        magnesium stearate   2                                                        ______________________________________                                    

The mixture is thoroughly blended to form a uniform powder. Measurevolumes of the powder, corresponding to 150 mg by weight, are compressedinto tablets containing the desired potency of each active ingredient.

EXAMPLE 14 Tablets--Piroxicam (20 mg) and Acetaminophen (500 mg)

The following ingredients are combined in the following proportions byweight:

    ______________________________________                                        piroxicam            20                                                       acetaminophen        500                                                      lactose              1035                                                     hydroxypropyl methylcellulose                                                                      10                                                       sodium starch glycollate                                                                           25                                                       magnesium stearate   10                                                       ______________________________________                                    

The mixture is blended to a uniform powder and compressed into tabletsin measured volumes corresponding to 1600 mg by weight to yield tabletsof the desired potency in each drug.

EXAMPLE 15 Capsules--Piroxicam (20 mg) and Trimazosin (40 mg)

The following ingredients are combined in the following proportions byweight:

    ______________________________________                                        piroxicam          20                                                         trimazosin hydrochloride                                                      monohydrate        45     (equivalent to                                                                40 of free base)                                    cornstarch         632                                                        magnesium stearate 3                                                          ______________________________________                                    

The mixture is thoroughly blended so as to obtain a uniform powder. Theresultant mix (700 mg fill weight) is filled into hard gelatin capsulesof a suitable size so as to obtain capsules of the desired potency ineach drug.

We claim:
 1. A method for reducing gastric irritation or ulceration in amammal being treated with an anti-inflammatory effective amount otpiroxicam or a pharmaceutical acceptable salt thereof which comprisescoadministration of acetaminophen or a pharmaceutically acceptable saltthereof in an amount which reduces said gastric erritation orulcerations.
 2. A method of claim 1 wherein the acetaminophen is in itsfree phenolic form.
 3. A method of claim 1 wherein the piroxicam is inits free enolic form.
 4. A method of claim 1 wherein the piroxicam isinthe form of its ethanolamine salt.